The pharmaceutical industry has used fluid-bed granulation extensively for several decades to improve powder properties (e.g., flowability and compressibility) for downstream processing. During this two-phase process that includes spraying and drying, the addition of a binder liquid causes primary particles to aggregate and form granules (1). The granule size distribution (GSD) is of major importance to the final quality of the granulated product because it influences density, flowability, and dustiness. Hence, the understanding and control of granule growth during manufacturing are of major importance to the delivery of a high-quality end product.

Sieve analysis, image analysis, and laser diffraction are common off-line particle-size determination techniques. These methods are usually time-consuming and labor-intensive because they require sample preparation. In recent years, interest in real-time process analysis has increased, partly because of FDA's process analytical technology (PAT) initiative. Several studies have examined at-line, on-line, and in-line particle-size analysers. The application of image analysis, near-infrared spectroscopy, acoustic-emission spectroscopy, focused-beam reflectance spectroscopy, and spatial-filter velocimetry for real-time granulation monitoring has been investigated (2–24).

The authors applied spatial-filter velocimetry (SFV) in-line during top-spray fluid-bed granulation to obtain GSD information continuously. During SFV measurements, particles pass through a laser beam, and the corresponding shadow thrown onto the detector helps determine the chord-length distribution of the measured particles. The measurement zone at the probe tip is equipped with sapphire windows that are kept clean by an internal compressed-air supply system, thus preventing window fouling. A two-level full-factorial design was used to examine the influence of process and formulation variables on end product GSD, measured in-line with SFV and compared with off-line laser diffraction (LD) results. The granule-size data obtained continuously in-line were analyzed in detail to improve understanding of the influence of the examined process and formulation variables on the granule growth mechanism. Furthermore, the in-line quantified GSD was related to the off-line-measured tapped density using univariate, multivariate, and multiway models, thus allowing early estimation of this end-product property during granulation.

Materials and methods

Table I: Lower and upper levels of the examined process and formulation variables.

Materials. The dry powder mass consisted of dextrose monohydrate (700 g, Roquette Frères) and unmodified maize starch (Cargill Benelux). This was granulated with an aqueous binder solution of hydroxypropyl methylcellulose (HPMC, type 2910, 15 mPa, Dow Chemical) and Tween 20 (Croda Chemicals Europe). The amounts of HPMC and Tween 20 were varied according to the design of experiments (DOE, see Table I). The HPMC binder was always sprayed as a 4% solution, and the total amount of solids was kept constant at 1 kg by varying the amount of maize starch accordingly.

Fluid-bed granulation set-up. Granulations were performed in a laboratory-scale fluid-bed granulator (GPCG 1, Glatt). An SFV probe (Parsum IPP 70; Gesellschaft für Partikel-, Strömungs- und Umweltmesstechnik) was installed in the fluid-bed granulator at a height of 200 mm above the distributor plate and at approximately 50 mm from the side wall of the granulator. Granules passed through a 4-mm aperture, and an internal and external air connection prevented fouling of the measurement zone and ensured the dispersion of the powder mass. SFV data were collected every second during the entire granulation processes, but an average granule-size distribution was saved every 10 s. The granulation process finished when an outlet air temperature of 37 °C and a product temperature of 45 °C were reached.

DOE. A two-level full-factorial design was applied to study the effects of HPMC concentration, Tween 20 concentration, inlet-air temperature during spraying, and inlet-air temperature during drying (see Table I) on the end-product's GSD. Three design center point repetitions were performed (i.e., 19 experiments in total).

Off-line granule characterization. For each DOE granulation experiment, the end-product particle-size distribution was determined with LD (Mastersizer S long bench, Malvern Instruments). Average D10, D50, and D90 values were determined based on three measurements of each batch.

End-product tapped-density measurements (1250 taps, J. Englesmann) were performed in triplicate, and the average tapped density was used.